Endometrial cancer affects more than 40,000 women per year. The incidence of endometrial cancer is rising as life expectancy increases and as key risk factors, including obesity, becomes more prevalent. Chronic exposure to estrogen with a lack of opposing progesterone is highly associated with endometrial carcinoma. Progesterone is a hormone that antagonizes the growth-promoting properties of estrogen in the uterus. Progesterone therapy has been shown to be effective in preventing endometrial cancer as well as controlling growth of the endometrium. However, the effectiveness of progestins for women with endometrial cancer is less clear. Progesterone functions through its receptor (PR), and regulates the expression of genes. For PR to do this, it must be properly phosphorylated at specific residues. Furthermore, its transcriptional function is dependent on the cofactors that are available. Interestingly, up to 80% of endometrial cancers carry a PTEN mutation. Given the role of PTEN to negatively regulate the PI3K/AKT pathway, inactivation of this gene results in hyper activated AKT, which contributes to enhanced proliferation and survival. In the proposed project, we will study the post translational modification of PR, its transcriptional function and the physiological role in the context of hyper activated AKT. This will be done using the most current technologies, using in vitro and in vivo models to study tumor behavior in response to progesterone and inhibitors of the AKT pathway. The information generated from this study may contribute towards the development of combinatorial therapies using hormones and inhibitors of the AKT pathway. PUBLIC HEALTH RELEVANCE: Progestin therapy is an attractive option for women with endometrial adenocarcinoma who want to preserve fertility or cannot undergo surgery. This option is vital since risk factors for endometrial cancer such as obesity are on the rise and are affecting younger women. This project focuses on understanding how the AKT pathway, which is a pathway that is overactive due to a common mutation in endometrial cancer, which affects progesterone receptor action. This is important to understand since only a subset of women with endometrial cancer responds to progestins. The data generated from this project will contribute towards improving progestin therapy in these progestin resistant women.